1. Field of the Invention
The invention relates to compositions for the control of adrenocortical disease in ferrets.
2. Description of the Prior Art
Adrenocortical disease (ACD) in ferrets (Mustela putorius furo) is a common problem in neutered, middle-aged to old ferrets. The adrenal tissues of these ferrets develop nodular hyperplasia, adenomas, or adenocarcinomas which occasionally results in death. The adrenal tissues of these ferrets also exhibit an increase in the production of a variety of steroid hormones, including estradiol, 17-hydroxyprogesterone, and androstenedione, to pathological levels. The major clinical signs attributable to these hormones are alopecia in both sexes and a swollen vulva in females. Pruritus, muscle atrophy, hind limb weakness, and sexual activity or aggression are observed less frequently. Males can develop prostatic cysts, prostatitis, and urethral obstruction. As the disease progresses, there is often a decrease in the apparent quality of life. Occasionally, adrenal gland tumors continue to grow, invade tissues locally, and become necrotic; rarely, they rupture causing death. Additional potentially fatal sequelae include metastases and bone marrow suppression associated with chronic exposure to high serum estrogen concentrations [Rosenthal & Peterson. Evaluation of plasma androgens and estradiol concentrations in ferrets with hyperadrenocorticism. J Am Vet Med Assoc. 1996. 209:1097-1102; Wagner & Dorn. Evaluation of serum estradiol concentrations in alopecic ferrets with adrenal gland tumors. J Am Vet Med Assoc. 1994. 205:703-707; Rosenthal et al. Hyperadrenocorticism associated with adrenocortical tumor or nodular hyperplasia of the adrenal gland in ferrets: 50 cases (1987-1991). J Am Vet Med Assoc. 1993. 203:271-275; and Weiss & Scott. Clinical aspects and surgical treatment of hyperadrenocorticism in the domestic ferret: 94 cases (1994-1996). J Am Anim Hosp Assoc. 1997. 33:487-493].
ACD is thought to be due to an increase LH concentration, often present in neutered ferrets, with acts on the luteinizing hormone (LH) receptors on the adrenocortex resulting in adrenal gland hyperplasia, tumor induction and growth, and increased steroid hormone secretion. There is speculation that the high prevalence of ACD in pet ferrets is associated with neutering at an early age, and may be a result of chronic stimulation of the adrenal gland cortex by pituitary gland gonadotropins (i.e., follicle stimulating hormone [FSH] and LH) (Rosenthal & Peterson. ibid; Shoemaker et al. Correlation between age at neutering and age at onset of hyperadrenocorticism in ferrets. J Am Vet Med Assoc. 2000. 216:195-197; and Shoemaker et al. The role of luteinizing hormone in the pathogenesis of hyperadrenocorticism in neutered ferrets. Mol and Cell Endocrinol. 2002. 197:117-125). Exposure to abnormally long photoperiods associated with indoor housing of pet ferrets is also thought to contribute to the pathogenesis of ACD. Long light cycles of >8 hours have been shown to stimulate production of gonadotropin-releasing hormone (GnRH) and LH and decrease serum melatonin concentrations, a known antigonadotropic hormone in ferrets [Jallageas et al. Differential photoperiodic control of seasonal variations in pulsatile luteinizing hormone release in long-day (ferret) and short-day (mink) mammals. J Bio Rhythms. 1994. 9(3-4):217-231].
Down regulation of GnRH receptors and subsequent suppression of the production and release of these gonadotropins have been shown to reduce specific hormone production and eliminate hormone effects in ferrets [Wagner et al. Leuprolide acetate treatment of adrenal cortocal disease in ferrets. J Am Vet Med Assoc 2001; 218 (8): 1272-1274; and Wagner et al. Clinical observations and endocrine response to treatment of adrenal cortical disease in ferrets with GnRH (deslorelin acetate) implants. Am J Vet Res 2005; 66 (5): 910-914]. In humans, GnRH analogs administered at pharmacologic doses downregulate GnRH receptors at the pituitary gland.
Gonadotropin-releasing hormone agonists are a relatively new class of drugs, which, when chronically administered, result in marked reductions in blood levels of testosterone and estrogen. These drugs include leuprolide acetate, nafarelin acetate, deslorelin and goserelin acetate. Approved indications for these drugs, depending on the specific agent, include advanced prostate cancer, endometriosis, and precocious puberty. At high doses, GnRH agonists causes downregulation of GnRH receptors at the pituitary gland, thereby inhibiting production and release of gonadotropins (LH and FSH). However, GnRH agonists have a relative short effectiveness and must be delivered in a slow release implant. This implant must be replaced every 12-13 months depending on the mg of drug in the implant.